Lysosomal Destabilization Contributes to Apoptosis of Germinal Center B-lymphocytes

Abstract

S U M M A R Y During germinal center (GC) reactions, B-lymphocytes with high-affinity B-cell receptors are selected. Regulation of apoptosis is a key process in selecting such wanted B-cells and in eliminating B-cells with unwanted specificities. In this paper, we show that apoptosis in human GC B-cells involves lysosomal destabilization, which is strictly controlled by caspase-8 activity, but not by caspase-9 activity. Ligation of CD40 provides resistance to lysosomal destabilization. Experimental lysosomal rupture by the lysosomotropic drug O-methyl-L-serine dodecylamide hydrochloride (MSDH) induces apoptosis in GC B-cells, including phosphatidyl serine exposure, mitochondrial inactivation, and DNA fragmentation. These apoptotic features occur in the absence of caspase-3 activity. Follicular dendritic cells (FDCs) protect binding B-lymphocytes from lysosomal destabilization, in both the absence and the presence of MSDH. Our study demonstrates that lysosomal leakage induces apoptosis of GC B-cells in a caspase-3-independent manner and that high-affinity binding to FDCs prevents lysosomal leakage and apoptosis in GC B-cells.

Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages

“…Afterward this detergent has been found to induce lysosomal rupture and apoptosis in several different types of cell models [14,15]. It remains unknown whether oxidative stress driven by lysosomal iron is involved in MSDH induced apoptosis.…”

Diverse regulatory roles for lysosomal proteases in the immune response

“…Like T cells, germinal centre B cells are subject to cathepsin-mediated apoptosis through their antigen receptors [84]. Interactions with follicular DC and CD40 ligation were shown to rescue B cells from LMP and apoptosis [85]. Further studies will be necessary to pin down the role of lysosomal enzymes and the mechanism of their escape from lysosomes during these processes.…”

The lysosomal stability as a biomarker for the determination of pollution in aquatic environments

“…Nowadays, the techniques that make use of the various components of the lysosomal compartment are increasingly being used in the monitoring of the effects of the anthropogenic toxic substances in the most diverse of species of the aquatic biota such as molluscs, crustaceans, fish, larva, worms, etc. Among them, the most reliable are those that evaluate the activity of the marker enzymes such as acid phosphatase (EC 3.1.3.2), β-N-acetylhexosaminidase (EC 3.2.1.52), cytochrome C oxidase (EC 1.9.3.1), neutral esterase (EC 3.1.1.1), cathepsin B (EC 3.4.22.1) and β-glucuronidase (EC 3.2.1.31) (Strömhaug et al, 1998, Petrovic et al, 2004, Marigómez et al, 2005and van Nierop et al, 2006. According to Koukouzika and Dimitriadis (2005), the assessment of the lysosomal stability, measured by the techniques related to the autophagy or endocytosis of the pigments, such as neutral red and cresyl violet, demonstrated the seasonal changes which depended on the species under the study, as well as on the inherent characteristics of the locations from where the specimens were collected.…”

“…They are also involved in cell defence mechanisms, in the protection against the toxic agents and infection by the viruses and bacteria (Cuervo and Dice, 2000). The physicochemical modifications which lead to the loss of the integrity of the membranes of diverse components of the lysosomes are almost always associated with cellular dysfunction, inflammatory and degenerative diseases as well as apoptosis and cell death (van Nierop et al, 2006). The aim of this work was to study the effects caused by five gasoline formulations on the stability of the membranes of the lysosomes isolated from the liver cells of young Nile tilapia (Oreochromis niloticus).…”